PSMD10/gankyrin induces autophagy to promote tumor progression through cytoplasmic interaction with ATG7 and nuclear transactivation of ATG7 expression

被引:121
作者
Luo, Tao [1 ,2 ]
Fu, Jing [1 ,2 ]
Xu, An [1 ,2 ]
Su, Bo [1 ]
Ren, Yibing [1 ,2 ]
Li, Ning [1 ]
Zhu, Junjie [1 ]
Zhao, Xiaofang [1 ]
Dai, Rongyang [1 ]
Cao, Jie [1 ]
Wang, Bibo [1 ]
Qin, Wenhao [1 ]
Jiang, Jinhua [1 ]
Li, Juan [4 ]
Wu, Mengchao [1 ]
Feng, Gensheng [1 ]
Chen, Yao [1 ,2 ]
Wang, Hongyang [1 ,2 ,3 ]
机构
[1] Eastern Hepatobiliary Surg Inst Hosp, Int Cooperat Lab Signal Transduct, Shanghai, Peoples R China
[2] Natl Ctr Liver Canc, Shanghai, Peoples R China
[3] Shanghai Jiao Tong Univ, Shanghai Canc Inst, Renji Hosp, State Key Lab Oncogenes & Related Genes,Sch Med, Shanghai, Peoples R China
[4] Changhai Hosp, Dept Nutr & Endocrinol, Shanghai, Peoples R China
基金
中国国家自然科学基金;
关键词
ATG7; autophagy; drug resistance; hepatocellular carcinoma; HSF1; PSMD10; sorafenib; HEAT-SHOCK FACTOR-1; HEPATOCELLULAR-CARCINOMA; CELL SURVIVAL; GANKYRIN; DEGRADATION; SORAFENIB; STRESS; NEURODEGENERATION; CHEMORESISTANCE; PROTEIN;
D O I
10.1080/15548627.2015.1034405
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Although autophagy is most critical for survival of cancer cells, especially in fast-growing tumors, the mechanism remains to be fully characterized. Herein we report that PSMD10/gankyrin promotes autophagy in hepatocellular carcinoma (HCC) in response to starvation or stress through 2complementary routes. PSMD10 was physically associated with ATG7 in the cytoplasm, and this association was enhanced by initial nutrient deprivation. Subsequently, PSMD10 translocated into the nucleus and bound cooperatively with nuclear HSF1 (heat shock transcription factor 1) onto the ATG7 promoter, upregulated ATG7 expression in the advanced stage of starvation. Intriguingly, the type of PSMD10-mediated autophagy was independent of the proteasome system, although PSMD10 has been believed to be an indispensable chaperone for assembly of the 26S proteasome. A significant correlation between PSMD10 expression and ATG7 levels was detected in human HCC biopsies, and the combination of these 2parameters is a powerful predictor of poor prognosis. The median survival of sorafenib-treated HCC patients with high expression of PSMD10 was much shorter than those with low expression of PSMD10. Furthermore, PSMD10 augmented autophagic flux to resist sorafenib or conventional chemotherapy, and inhibition of autophagy suppressed PSMD10-mediated resistance. We conclude that these results present a novel mechanism involving modulation of ATG7 by PSMD10 in sustaining autophagy, promoting HCC cell survival against starvation or chemotherapy. Targeting of PSMD10 might therefore be an attractive strategy in HCC treatment by suppressing autophagy and inducing HCC cell sensitivity to drugs.
引用
收藏
页码:1355 / 1371
页数:17
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